Metallothionein 2A Expression in Cancer-Associated Fibroblasts and Cancer Cells Promotes Esophageal Squamous Cell Carcinoma Progression

Esophageal cancer has the sixth highest mortality rate worldwide. Cancer-associated fibroblasts (CAFs) are involved in the progression of various cancers. Previously, we demonstrated an association between high expression of the CAF marker, fibroblast activation protein, and poor prognosis of esophageal squamous cell carcinoma (ESCC). We also established CAF-like cells by indirect co-culture of bone marrow-derived mesenchymal stem cells with ESCC cell lines and found metallothionein 2A (MT2A) to be highly expressed in them. Here, to explore the function of MT2A in CAFs, we silenced MT2A in the CAF-like cells and ESCC cell lines using small interfering RNA. MT2A knockdown in the CAF-like cells suppressed expression and secretion of insulin-like growth factor binding protein 2 (IGFBP2); recombinant IGFBP2 promoted migration and invasiveness of ESCC cells via NFκB, Akt, and Erk signaling pathways. Furthermore, MT2A knockdown in the ESCC cell lines inhibited their growth, migration, and invasiveness. Immunohistochemistry demonstrated that high MT2A expression in the cancer stroma and cancer nest of ESCC tissues correlated with poor prognosis of ESCC patients. Hence, we report that MT2A in CAFs and cancer cells contributes to ESCC progression. MT2A and IGFBP2 are potential novel therapeutic targets in ESCC.

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Urokinase plasminogen activator secreted by cancer-associated fibroblasts induces tumor progression via PI3K/AKT and ERK signaling in esophageal squamous cell carcinoma

Oncotarget ◽

10.18632/oncotarget.15857 ◽

2017 ◽

Vol 8 (26) ◽

pp. 42300-42313 ◽

Cited By ~ 12

Author(s):

Baoqing Tian ◽

Xiaojia Chen ◽

Huihua Zhang ◽

Xiaoyan Li ◽

Jiakang Wang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Tumor Progression ◽

Cell Carcinoma ◽

Plasminogen Activator ◽

Squamous Cell ◽

Urokinase Plasminogen Activator ◽

Erk Signaling ◽

Cancer Associated Fibroblasts

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PS02.200: A COMPREHENSIVE SCREENING OF THE FRA-1 REGULATORY GENES IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Diseases of the Esophagus ◽

10.1093/dote/doy089.ps02.200 ◽

2018 ◽

Vol 31 (Supplement_1) ◽

pp. 179-179

Author(s):

Takeshi Toyozumi ◽

Isamu Hoshino ◽

Haruhito Sakata ◽

Kentaro Murakami ◽

Masayuki Kano ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Candidate Genes ◽

Cell Lines ◽

Squamous Cell ◽

Poor Prognosis ◽

Primary Tumors ◽

Expression Levels ◽

Hmga1 Expression

Abstract Background The expression of Fos-related antigen 1 (Fra-1) affects tumor progression, migration and invasion. We previously reported that a high Fra-1 expression level is associated with lymph node metastasis and a poor prognosis in patients with esophageal squamous cell carcinoma (ESCC). In this study, we identified the genes regulated by Fra-1 in ESCC. Methods We constructed Fra-1 knockdown models via the transfection of small interfering RNA (siRNA) into ESCC cell lines (TE10, TE11). The expression levels of the genes in the knockdown models were analyzed using a microarray experiment and Biobase Upstream Analysis (Cytoline Solutions, Tokyo, Japan), and candidate genes regulated by Fra-1 in the ESCC cell lines were detected. The actual connection of Fra-1 to the promoter region was identified in a ChIP-PCR experiment. The expression levels of the candidate genes regulated by Fra-1 in the primary tumors of surgical specimens obtained from ESCC patients (n = 135) were compared to those observed in normal tissues using real-time PCR and immunohistochemical staining, and the clinicopathological features were analyzed. Results The results of the Biobase Upstream Analysis and ChIP-PCR showed high mobility group protein 1 (HMGA1) and hyaluronan mediated motility receptor (HMMR) to be significant genes regulated by Fra-1. The expression levels of both HMGA1 and HMMR were found to closely correlate with the Fra-1 expression in the clinical specimens. The patients with a positive HMGA1 expression had a poorer prognosis than those with a negative expression (P = 0.017) and the patients with positive HMMR expression also had a poorer prognosis (P = 0.018). Moreover, a multivariate analysis demonstrated a positive HMGA1 expression to be a significant independent prognostic factor in the ESCC patients. Conclusion HMGA1 and HMMR are regulated by Fra-1 in the setting of ESCC and the HMGA1 expression is significantly associated with a poor prognosis in ESCC patients. Downregulating the HMGA1 and HMMR expression may become a practical treatment strategy against ESCC in the future. Disclosure All authors have declared no conflicts of interest.

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Stem Cell Markers CXCR-4 and CD133 Predict Aggressive Phenotype and Their Double Positivity Indicates Poor Prognosis of Oral Squamous Cell Carcinoma

Cancers ◽

10.3390/cancers13235895 ◽

2021 ◽

Vol 13 (23) ◽

pp. 5895

Author(s):

Ravindran Caspa Gokulan ◽

Halagowder Devaraj

Keyword(s):

Squamous Cell Carcinoma ◽

Stem Cell ◽

Oral Cancer ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Cancer Cells ◽

Cell Lines ◽

Squamous Cell ◽

Poor Prognosis ◽

Oral Cancer Cells

The activation of the SDF-1/CXCR-4 pathway is crucial for the invasion and metastasis of oral cancer cells. The CXCR-4 positive cells possess stem cell characteristics and express the cancer stem cell marker, CD133, in tumors of colon and pancreas. Despite several studies, the co-expression of CXCR-4 and CD133 and its significance is still largely unknown in oral cancer. Therefore, we aimed to investigate the impact of CXCR-4 and CD133 double positivity in the prognosis of oral cancer. The significance of PKC-δ, one of the key signaling molecules that regulates CXCR-4, was also analyzed. Immunohistochemistry and double immunofluorescence was used to investigate the co-localization of CXCR-4, PKC-δ and CD133 in the human tissues and cell lines of oral squamous cell carcinoma. The expression of CXCR-4, PKC-δ and CD133 were found to be higher in poorly differentiated and lymph node metastasis-positive cases. Interestingly, CXCR-4 positive cells showed positive staining for PKC-δ and CD133 in oral cancer tissue and cell lines. Moreover, CXCR-4+/CD133+ and CXCR-4+/PKC-δ+ double positive cases have the worst survival. We discovered, for the first time, that patients with expression of both CXCR-4 and CD133 have a lower survival rate, and CXCR-4+/CD133+, as well as CXCR-4+/PKC-δ+ double positivity, can be utilized to predict poor prognosis. CXCR-4, PKC-δ and CD133 might regulate aggressiveness and invasion of oral cancer cells.

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DNA Polymerase Iota Promotes Esophageal Squamous Cell Carcinoma Proliferation Through Erk-OGT-Induced G6PD Overactivation

Frontiers in Oncology ◽

10.3389/fonc.2021.706337 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhenzi Su ◽

Aidi Gao ◽

Xiaoqing Li ◽

Shitao Zou ◽

Chao He ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Dna Polymerase ◽

Squamous Cell ◽

Poor Prognosis ◽

Erk Signaling ◽

Rapid Progression ◽

Dna Polymerase Iota ◽

Potential Biomarker

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers with rapid progression and a high mortality rate. Our previous study demonstrated that DNA polymerase iota (Pol ι) is overexpressed in ESCC tumors and correlates with poor prognosis. However, its role in ESCC proliferation remains obscure. We report here that Pol ι promotes ESCC proliferation and progression through Erk- O-GlcNAc transferase (OGT) regulated Glucose-6-phosphate dehydrogenase (G6PD) overactivation. Cell clonogenic ability was assessed by colony formation assay. Cell proliferation was assessed by EdU incorporation assay. Our transcriptome data was reanalyzed by GSEA and validated by analysis of cellular metabolism, G6PD activity, and cellular NADPH concentration. The level of Pol ι, OGT, G6PD and O-GlcNAcylation in ESCC cells and patient samples were analyzed. The MEK inhibitor PD98059 was applied to confirm OGT expression regulation by the Erk signaling. The G6PD inhibitor polydatin was used to examine the role of G6PD activation in Pol ι promoted proliferation. We found that Pol ι promotes ESCC proliferation. It shunted the glucose flux towards the pentose phosphate pathway (PPP) by activating G6PD through OGT-promoted O-GlcNAcylation. The expression of OGT was positively correlated with Pol ι expression and O-GlcNAcylation. Notably, elevated O-GlcNAcylation was correlated with poor prognosis in ESCC patients. Pol ι was shown to stimulate Erk signaling to enhance OGT expression, and the G6PD inhibitor polydatin attenuated Pol ι induced tumor growth in vitro and in vivo. In conclusion, Pol ι activates G6PD through Erk-OGT-induced O-GlcNAcylation to promote the proliferation and progression of ESCC, supporting the notion that Pol ι is a potential biomarker and therapeutic target of ESCC.

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